Cognitive function within a human brain

ABSTRACT

Methods and apparatus for improving cognitive function within a human. The invention utilizes an implanted device, such as an implantable signal generator or an implantable pump, to affect tissue elements within a Papez circuit of the human brain as well as tissue upstream or downstream from the Papez circuit. The implanted device delivers treatment therapy to thereby improve cognitive function by the human. A sensor may be used to detect various symptoms of the cognitive disorder. A microprocessor algorithm may then analyze the output from the sensor to regulate delivery of the stimulation and/or drug therapy.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/034,336 (Attorney Docket No. 41551-705.303), filed Sep. 23,2013, which is a continuation of U.S. patent application Ser. No.13/690,223, now U.S. Pat. No. 8,565,883 (Attorney Docket No.41551-705.302), filed Nov. 30, 2012, which is a continuation of U.S.patent application Ser. No. 13/094,320, now U.S. Pat. No. 8,346,365(Attorney Docket No. 41551-705.301), filed Apr. 26, 2011, which is acontinuation of U.S. patent application Ser. No. 11/303,293, now U.S.Pat. No. 8,000,795 (Attorney Docket No. 41551-705.201), filed Dec. 16,2005, which claims priority to U.S. Provisional Application No.60/636,988 (Attorney Docket No. 41551-705.101), filed Dec. 17, 2004,each of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to techniques for providing treatmenttherapy to improve cognitive function within a brain of a human by wayof brain stimulation and/or drug infusion.

Cognitive disorders are a common type of neurological disorders. Forexample, dementia is form of impaired cognition caused by braindysfunction. The hallmark of most forms of dementia is the disruption ofmemory performance. Among the several conditions labeled as dementia,the most common are Alzheimer's disease and mild cognitive impairment(MCI), which is a pre-clinical form of Alzheimer's disease. MCI is anintermediate state between normal aging and dementia and ischaracterized by acquired cognitive deficits, without significantdecline in functional activities of daily living. Subjects with MCI andthe initial phase of Alzheimer's disease originally present with apredominant deficit in memory function. In more advanced stages ofAlzheimer's disease, impairment in additional cognitive domainsculminate with a significant decline in quality of life and theinability to perform usual daily activities.

Alzheimer's disease is one of the most common cognitive disorders inhumans and has an exponentially increasing incidence. Although thedefining characteristic of Alzheimer's disease is cognitive impairment,it is often accompanied by mood and behavioral symptoms such asdepression, anxiety, irritability, inappropriate behavior, sleepdisturbance, psychosis, and agitation. Neuro-imaging and genetic testinghave aided in the identification of individuals at increased risk fordementia. However, the measurement of change in cognitive and functionalstatus in, for example, MCI remains challenging because it requiresinstruments that are more sensitive and specific than those consideredadequate for research in dementia. Accordingly, no treatment exists thatadequately prevents or cures Alzheimer's disease or MCI.

Alzheimer's disease and MCI are already a public health problem ofenormous proportions. It is estimated that 5 million people currentlysuffer with Alzheimer's disease in the United States. This figure islikely underestimated due to the high number of unrecognized andundiagnosed patients in the community. By the year 2050, Alzheimer's isprojected to affect 14 million people. Moreover, because the prevalenceof Alzheimer's disease doubles every 5 years after age 65, the impact ofthe disease on society tends to increase with the growth of the elderlypopulation. The annual cost in the United States of AD alone isapproximately $100 billion.

There is currently no effective treatment for the memory loss and othercognitive deficits presented by patients with dementia, particularlyAlzheimer's disease. Treating Alzheimer's disease tends to be morechallenging than other neurological disorders because Alzheimer'slargely affects a geriatric population. Oral medications includingAcetylcholinesterase inhibitors and cholinergic agents are the mainstaytreatment for this condition. Nevertheless, the outcome with theseagents is modest and tends to decline as the disease progresses. Otheragents, such as nonsteroidal anti-inflammatory drugs, corticosteroids,COX-2 inhibitors, estrogen, and antioxidants, have also been tried withpoor results. Neurotrophic factors (molecules that increase survival andgrowth of neurons in laboratory experiments) have been recently usedclinically for Alzheimer's disease. Because these agents are proteins,they are inactive with oral administration and cannot cross theblood-brain barrier when administered systemically. When infusedintraventricularly in three patients with Alzheimer's disease, nervegrowth factor (NGF) increased cerebral nicotine binding. However, thiscompound had only modest clinical effects and was associated with backpain and weight loss that were reversible with the cessation oftreatment.

Alternative routes of neurotrophic factor administration are currentlybeing studied. Gene therapy and small neurotrophic molecules that canpenetrate the blood-brain barrier (AIT-082) are possible methods fordrug delivery. Moreover, treatment strategies against beta-amyloidprotein accumulation and plaque formation including immunotherapies withvaccines are other possible methods. However, but clinical data is stilllacking for any of these alternative methods for treating cognitivedisorders.

Most aspects of memory function involve temporal lobe structures.Amnesic syndromes have been described after the disruption of thehippocampus, amygdala, formix, mammilary bodies, anterior nucleus of thethalamus, rhinal cortex, parahippocampal cortex, and temporal neocortex.These structures are mainly involved with the so-called declarativememory, which comprises the memory for facts, events, spatial location,recognition of forms, significance of data processed, among others.However, no interventions within the temporal lobe have been successfulin improving memory function.

The hippocampus also has been found to play a crucial role in learningand memory. Lesions of the hippocampus in rodents, primates and man havebeen found to impair the process of memory acquisition and itspersistence. In addition, the hippocampus receive strong inputs fromnuclei in the basal forebrain, including the septal nuclei, the diagonalband of Broca and the nucleus basalis of Meynert and lesions in thesestructures also impair learning and memory. Dysfunction or pathologicalchanges in these circuits may contribute to memory and learning deficitsin a variety of circumstances including old age and Alzheimer's disease.The finding of pathological changes in these structures (includingsynaptic and neuronal loss, senile plaques and neurofibrillary tangles)is characteristic of both age related and Alzheimer's type memory andlearning dysfunction. Since septohippocampal lesions affect new learningto a greater extent than established memories, these structures appearto play an essential facilitory role in the establishment andconsolidation of memory. Again, however, no interventions within thehippocampus or related structures have been successful in improvingmemory function.

It is therefore desirable to provide a technique for preventing ortreating cognitive disorders such as Alzheimer's disease and/or, morebroadly, to improve cognitive function in patients.

BRIEF SUMMARY OF THE INVENTION

An embodiment of the invention uses electrical stimulation of the Papezcircuit and/or tissue upstream to or downstream from the Papez circuitto improve cognitive function. The treatment is carried out by animplantable signal generator and at least one implantable electrodehaving a proximal end coupled to the signal generator and having astimulation portion for electrically affecting tissue elements of aPapez circuit or upstream/downstream tissue. Alternatively, thetreatment may be carried out by an implantable pump and at least onecatheter having a proximal end coupled to the pump and having adischarge portion for infusing therapeutic dosages of the one or moredrugs into a predetermined infusion site in neural tissue. By using theforegoing techniques, cognitive function within a human can besignificantly improved including, for example, patients suffering fromAlzheimer's and MCI. In other embodiments of the invention, druginfusion may be used as treatment therapy in addition to the electricalstimulation.

In another embodiment of the invention, a sensor is used in combinationwith the signal generator and/or implantable pump to treat the cognitivedisorder. In this form of the invention, the sensor generates a sensorsignal related to extent of the cognitive disorder.

The implanted device is responsive to the sensor signal to regulate thesignal generator and/or pump so that the neurological disorder istreated.

By using the foregoing techniques, cognitive disorders can be controlledor treated to a degree unattainable by prior art methods or apparatus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic illustration of an electrode implanted in abrain according to an embodiment of the present invention and a signalgenerator coupled to the electrode.

FIGS. 2 and 2A are diagrammatic illustrations of a catheter implanted ina brain according to an embodiment of the present invention.

FIG. 3 is a schematic block diagram of a microprocessor and relatedcircuitry of an implantable medical device for use with the presentinvention.

FIG. 4 is a diagram depicting the various components of the Papezcircuit. FIGS. 4A and 4B illustrate specific components of the Papezcircuit.

DETAILED DESCRIPTION OF THE INVENTION

The invention discloses techniques for delivering treatment therapy toPapez circuit of a human brain to improve cognitive function. Theapplicant has discovered that cognitive function can be improved throughdelivery of treatment therapy to the Papez circuit and/or tissueupstream to or downstream from the Papez circuit. Accordingly, theinvention incorporates electrical stimulation and/or drug infusiontechniques to directly or indirectly influence tissue elements withinthe Papez circuit. One or more electrodes and/or catheters are implantedin the brain so that the stimulation or infusion portions lie within orin communication with predetermined portions of the brain. Theelectrical stimulation or drug therapy influences the Papez circuit toachieve the desired result.

These techniques of the present invention are suitable for use withinany implantable medical device. In an embodiment, the present inventionis implemented within an implantable neurostimulator system, however,those skilled in the art will appreciate that the present invention maybe implemented generally within any implantable medical device systemincluding, but not limited to, implantable drug delivery systems,implantable systems providing stimulation and drug delivery.

In addition, the present invention may be embodied in various forms toanalyze and treat cognitive disorders. Such disorders include, forexample without limitation, Alzheimer's disease, MCI, dementia, amnesiaand memory disorders as can occur after injury, trauma, stroke, cranialirradiation, and in the context of genetic, congenital, infectious,autoimmune, toxic (drugs and alcohol), nutritional (vitamindeficiencies) metabolic, inflammatory, neurodegenerative neoplastic oridiopathic processes involving the brain. Some additional specificdisorders where the therapy of the invention may be useful include:amnestic syndromes, Werkicke-Korsakoff and Korsakoff syndromes, Herpesencephalitis, severe hypoxia, vascular disorders, head injury, transientglobal amnesia, global amnesia epileptic amnesia, cerebral palsy,autism, mental retardation and attention deficit and hyperactivitydisorders.

Referring to FIG. 1, an implantable neurostimulator device 16 made inaccordance with an embodiment may be implanted below the skin of apatient. A lead 522A is positioned to stimulate a specific site 525 in abrain (B). Device 16 may take the form of a modified signal generatorModel 7424 manufactured by Medtronic, Inc. under the trademark Itrel IIwhich is incorporated by reference. Lead 522A may take the form of anyof the leads sold with the Model 7424 such as Model 3387, forstimulating the brain, and is coupled to device 16 by a conventionalconductor 522. One or more external programmers (not shown) may beutilized to program and/or communicate bi-directionally with theimplanted device 16.

As shown, the distal end of lead 522A terminates in four stimulationelectrodes implanted into a portion of the brain by conventionalstereotactic surgical techniques. Each of the four electrodes isindividually connected to device 16 through lead 522A and conductor 522.Lead 522A is surgically implanted through a hole in the skull 123 andconductor 522 is implanted between the skull and the scalp 125 as shownin FIG. 1. Conductor 522 is joined to implanted device 16 in the mannershown. Referring to FIG. 2A, device 16 is implanted in a human body 120in the location shown. Body 120 includes arms 122 and 123.Alternatively, device 16 may be implanted in the abdomen. Conductor 522may be divided into twin leads 522A and 522B that are implanted into thebrain bilaterally as shown. Alternatively, lead 522B may be suppliedwith stimulating pulses from a separate conductor and signal generator.Leads 522A and 522B could be 1) two electrodes in two separate nucleithat potentiate each others effects or 2) nuclei with opposite effectswith the stimulation being used to fine tune the response throughopposing forces. It will be appreciated, however, that any number ofelectrodes may be implanted within the brain in accordance with theinvention. Additionally, one or more secondary electrodes may beimplanted so that a secondary stimulation portion lies in communicationwith another predetermined portion of a brain. Moreover, as will bediscussed below, one or more catheters, coupled to a pump, may beimplanted so that a secondary stimulation portion lies in communicationwith the tissue elements of the Papez circuit.

The targeted treatment site is the Papez circuit or, more generally, anysite that affects neural tissue within the Papez circuit. The Papezcircuit is generally a neuronal circuit in the limbic system, consistingof the hippocampus, formix, mammillary body, anterior thalamic nuclei,and cingulate gyrus. FIGS. 4, 4A and 4B depict the various elements ofthe Papez circuit. In an embodiment, hypothalamic stimulation withbilaterally implanted electrodes could modulate memory function andactivate limbic structures. Hypothalamic stimulation may evokesensations of deja vu, vague flashes of memory, and result in asignificant improvement in memory.

Moreover, the invention envisages the treatment of memory deficitsthrough the electrical stimulation of brain locations that are upstreamfrom the Papez circuit (i.e., structures that project to the Papezcircuit) and/or downstream from the Papez circuit (i.e., structures thatreceive inputs from Papez circuit). For example, the treatment therapymay affect temporal lobe structures, namely the, the septal nuclei, thesepto-hippocampal pathway, hippocampus; amygdala; fimbria/formix; thehypothalamus including the mammilary bodies; the medial forebrainbundle, mammilothalamic tract; anterior and mediodorsal nuclei of thethalamus; entorhinal, perirhinal and parahippocampal cortices; temporalstem and temporal white matter; and temporal neocortex, the amygdala,the diagonal band of the Broca. In addition, stimulation could beapplied to the cingulate cortex and to frontal lobe structures and tothe basal forebrain. Because stimulation in the nervous system is thoughto affect mostly axonal projections and fiber pathways, an embodimentenvisages stimulating the formix or mammilothalamic tracts.

Examples of upstream structures that project onto the Papez circuit thatcould also be affected include the regions that provide input to thehippocampus such as nuclei in the basal forebrain, including the septalnuclei, the diagonal band of Broca and the nucleus e of Meynert. Each ofthese structures and the neural structures that in turn modify theiractivity (particularly, the locus ceruleus catecholaminergic system, thebrainstem raphe serotonergic system, the brainstem cholinergic systemand the mesolimbic dopaminergic system) are potential sites ofintervention through the use of electrical stimulation or drug infusionto reward, reinforce and enhance learning and memory. As discussedherein, reference to the Papez circuit may also include tissue upstreamto or downstream from the Papez circuit.

The device 16 may be operated to deliver stimulation to the tissueelements of the Papez circuit to thereby improve cognitive function bythe human. The particular stimulation delivered may be performed byselecting amplitude, width and frequency of stimulation by theelectrode. The possible stimulations include between 0 Hertz and 300Hertz for frequency, between 0 Volts and 10 Volts for pulse amplitude,and between 0 .mu.Seconds and 400 .mu.Seconds for pulse width.

In an embodiment, bipolar stimulation of the hypothalamus may beutilized with the following stimulation parameters −2.8 V bilaterally,60 .mu.sec, and 130 Hz with contacts 0 and 4 as cathodes, and contacts 1and 5 as anodes. In another embodiment, monopolar stimulation of thehypothalamus may be utilized with the following stimulation parameters−2.8 V bilaterally, 60 .mu.sec, 130 Hz, contacts 0 and 4 as negative andthe case as positive.

Referring to FIG. 2, in another embodiment, the system or device of thepresent invention may utilize drug delivery as the form of treatmenttherapy. A pump 10 may be implanted below the skin of a patient. Thepump 10 has a port 14 into which a hypodermic needle can be insertedthrough the skin to inject a quantity of a liquid agent, such as amedication or drug. The liquid agent is delivered from pump 10 through acatheter port 20 into a catheter 422. Catheter 422 is positioned todeliver the agent to specific infusion sites in a brain (B). Pump 10 maytake the form of any number of known implantable pumps including forexample that which is disclosed in U.S. Pat. No. 4,692,147.

The distal end of catheter 422 terminates in a cylindrical hollow tube422A having a distal end 425 implanted, by conventional stereotacticsurgical techniques, into a portion of the brain to affect tissue withinthe Papez circuit or a downstream target of the Papez circuit (discussedabove). Tube 422A is surgically implanted through a hole in the skulland catheter 422 is implanted between the skull and the scalp as shownin FIG. 2. Catheter 422 is joined to pump 10 in the manner shown. Pump10 is implanted in a human body in a subcutaneous pocket located in thechest below the clavicle. Alternatively, pump 10 may be implanted in theabdomen.

Catheter 422 may be divided into twin tubes 422A and 422B (not shown)that are implanted into the brain bilaterally. Alternatively, tube 422B(not shown) implanted on the other side of the brain may be suppliedwith drugs from a separate catheter and pump.

Any number of drugs may be administered including, but not limited to,an anesthetic, a GABA agonist, a GABA antagonist, a glutamateantagonist, a glutamate agonist, a degrading enzyme, a reputake blocker,and a dopamine antagonist. An activating chemical may be used andincludes any chemical that causes an increase in the discharge rate ofthe projection nerve cells from a region. An example (for projectionneurons which receive glutamatergic excitation and GABA inhibition)would be an agonist of the transmitter substance glutamate (facilitatingthe excitation) or a GABA antagonist (blocking the inhibition).Conversely, a blocking chemical may be used and includes any chemicalthat inhibits the projection neurons thereby causing a decrease in thedischarge rate of the projection nerve cells from a region. An examplewould be a glutamate antagonist (blocks excitatory input to theprojection nerve cells) or a GABA agonist (enhances inhibition of theprojection neurons).

A combination of treatment therapies may be delivered to provideinfluencing of various neuronal types. For example, it may be desirableto concurrently influence, via drug and/or electrical stimulation, theneurons in the hippocampus and other portions of the Papez circuit toachieve an improved result. Such a device to utilize both forms oftreatment therapy may be that which is disclosed, for example, in U.S.Pat. No. 5,782,798. In addition to affecting the Papez circuit, it maybe desirable to affect concurrently other portions of the brain.

Referring to FIG. 3, the overall components of the implanted device 16are shown (similar components may also be found for pump 10). Thestimulus pulse frequency is controlled by programming a value to aprogrammable frequency generator 208 using bus 202. The programmablefrequency generator provides an interrupt signal to microprocessor 200through an interrupt line 210 when each stimulus pulse is to begenerated. The frequency generator may be implemented by model CDP1878sold by Harris Corporation. The amplitude for each stimulus pulse isprogrammed to a digital to analog converter 218 using bus 202. Theanalog output is conveyed through a conductor 220 to an output drivercircuit 224 to control stimulus amplitude.

Microprocessor 200 also programs a pulse width control module 214 usingbus 202. The pulse width control provides an enabling pulse of durationequal to the pulse width via a conductor 216. Pulses with the selectedcharacteristics are then delivered from device 16 through cable 522 andlead 522A to the Papez circuit and/or other regions of the brain.

At the time the stimulation device 16 is implanted, the clinicianprograms certain key parameters into the memory of the implanted devicevia telemetry. These parameters may be updated subsequently as needed.

Hypothalamic stimulation has been found to modulate memory function andactivate limbic structures. In particular, high frequency stimulation ofthe distal electrode contacts in the operating room and during theinitial programming sessions evoked sensations of deja vu and vagueflashes of memory for the patient. After stimulation, the patient hadshown significant improvements in memory tests that depended onhippocampal function. In particular, neuropsychological assessmentconducted prior to the implantation of the DBS systems and 3 weeks afterthe electrodes were turned on revealed clear improvements on tests forlearning and retention. In addition, post-operative associativerecognition tasks revealed an increase in recollective retrieval withmonopolar stimulation. Evoked responses were recorded with anelectroencephalogram and reconstructed as low-resolution electromagnetictomographic images. Source analysis showed that hypothalamic stimulationwas spreading to the temporal lobes.

In particular, on the morning of the surgery, a stereotactic frame wasapplied to the patient's head under local anesthesia and a CT scan wasobtained (MRI may also be used). The choice of the hypothalamic target(the ventromedial nucleus of the hypothalamus) to be stimulated was madebased on indirect measurements from stereotactic atlas images relativeto the anterior and posterior commissures. Deep brain stimulationelectrodes (Medtronic model 3387; Medtronic, Minneapolis, Minn.) werebilaterally implanted and the four contacts of each of these electrodeswere tested in the operating room. These contacts were numbered from 0-3(right side) and 4-7 (left side), 0 and 4 being the most distal contactsand 3 and 7 the most proximal ones. The tips of the electrodes werepositioned in a region where cells could still be recorded duringmicrorecording mapping.

Sensations of deja vu were reported with unilateral monopolarstimulation (cathode contact; anode case) of the two more distalcontacts in each electrode (0, 1, 4 and 5), at 130 Hz, 60 microsecondsof pulse width, and a threshold of 3-5 volts. Five months after theprocedure, the patient returned for initial programming. With similarsettings, the inventor was able to reproduce the stimulation relatedeffects observed previously in the operating room. Deja vu sensationsoccurred with high frequency stimulation when the most distal contacts(numbers 0 and 4) were activated. The threshold for this effect was 3.8Von each side of the brain.

The patient was programmed with the following parameters: Monopolarstimulation (cathode 0 and 4, anode case), 2.8V bilaterally, 130 Hz, and60 microseconds. The neuropsychological evaluation was repeated 3 weeksafter the electrodes were turned on. To assess the evoked responses andthe areas that were activated with hypothalamic stimulation, alow-resolution electromagnetic tomography (LORETA) was obtained 1 monthafter the DBS electrodes were turned on.

Examining the pre-operative and 3 weeks post-stimulation results,baseline findings demonstrate that the patient had average to highaverage performances in most cognitive domains (abstraction, workingmemory, speed of processing, problem-solving, learning and retention).Even though little change was seen comparing post-stimulation withbaseline scores, a clear improvement was observed on tests for learningand retention, such as the California Verbal Learning Test and thePetrides Spatial Learning Test.

At 4 months after operation, results were obtained of associativerecognition tasks recorded without stimulation, with bipolar stimulation(2.8 V bilaterally, 60.mu.sec., 130 Hz, contacts 0 and 4 cathodes, andcontacts 1 and 5 anodes) and with monopolar stimulation (2.8 Vbilaterally, 60 .mu.sec, 130 Hz, contacts 0 and 4 negative and casepositive). There was a clear increase in the relative frequency ofremember responses with monopolar stimulation, a condition/state that ismodulated by hippocampus (recollective retrieval of associativeinformation). Data from 10 healthy young volunteers have shown that therelative proportions of remember and know responses are respectively0.45 and 0.55 (vs. 0.7 an 0.3 in the test patient).

The embodiments of the present invention shown above are open-loopsystems. The microcomputer algorithm programmed by the clinician setsthe stimulation parameters of signal generator 16. This algorithm maychange the parameter values over time but does so independent of anychanges in symptoms the patient may be experiencing. Alternatively, aclosed-loop system discussed below which incorporate a sensor 130 toprovide feedback could be used to provide enhanced results. Sensor 130can be used with a closed loop feedback system in order to automaticallydetermine the level of electrical stimulation necessary to achieve thedesired level of improved cognitive function. In a closed-loopembodiment, microprocessor 200 executes an algorithm in order to providestimulation with closed loop feedback control. Such an algorithm mayanalyze a sensed signal and deliver the electrical of chemical treatmenttherapy based on the sensed signal falling within or outsidepredetermined values or windows, for example, for BDNF and otherneurotrophins (e.g., NGF, CNTF, FGF EGF, NT-3) and corticosteroids.

For example, in one embodiment, the patient may engage in a specifiedcognitive task and wherein the system measures one or morecharacteristics to determine if the sensed levels are at expectedthresholds. If one or more of the sensed characteristics are outside apredetermined threshold, the system may initiate and/or regulate thetreatment therapy to thereby enhance cognitive function.

In one embodiment, the system may be continuously providing closed-loopfeedback control. In another embodiment, the system may operate inclosed-loop feedback control based on a time of day (e.g., during hoursthat the patient is awake) or based on a cognitive task (e.g., when thepatient is working). In yet another embodiment, the system may beswitchable between open-loop and closed-loop by operator control.

In another embodiment, the stimulation or drug delivery could be appliedbefore, after and/or during the performance of a memory, cognitive ormotor task learning task to facilitate the acquisition of learning orconsolidation of the task and in so doing, accelerate the rate of memoryacquisition and learning and enhance its magnitude. For example, thestimulation or drug delivery may be provided before, during, or afterperiods when the patient is learning a new language or playing a newinstrument. Such therapy may be useful during the encoding,consolidation and/or retrieval phases of memory. The neuromodulationintervention, brain stimulation or drug delivery could occur before,after or simultaneously to the memory, cognitive of motor skill task.

In another embodiment, therapy may be provided in relation to a learningtask. For example, the stimulation or drug delivery could be appliedbefore, after and/or during the performance of a memory, cognitive ormotor task to facilitate the acquisition of learning or consolidation ofthe task. In so doing, the rate of memory acquisition and learning maybe accelerated and enhanced in magnitude. For example, the stimulationor drug delivery may be provided before, during, or after periods whenthe patient is learning a new language or playing a new instrument. Suchtherapy may be useful during the encoding, consolidation and/orretrieval phases of memory. The neuromodulation intervention, brainstimulation or drug delivery could occur before, after or simultaneouslyto the memory, cognitive of motor skill task.

In another aspect of the invention, treatment therapy may be utilized toenhance neurogenesis as a method of improving cognitive function.Techniques for enhancing neurogenesis through treatment therapy aredisclosed in a co-pending patent application entitled “EnhancingNeurogenesis Within A Human Brain,” filed concurrent with the instantapplication and incorporated herein by reference in its entirety.

Referring back to FIG. 3, the system may optionally utilize closed-loopfeedback control having an analog to digital converter 206 coupled tosensor 130. Output of the A-to-D converter 206 is connected tomicroprocessor 200 through peripheral bus 202 including address, dataand control lines. Microprocessor 200 processes sensor data in differentways depending on the type of transducer in use and regulates delivery,via a control algorithm, of electrical stimulation and/or drug deliverybased on the sensed signal. For example, when the signal on sensor 130exceeds a level programmed by the clinician and stored in a memory 204,increasing amounts of stimulation may be applied through an outputdriver 224. In the case of electrical stimulation, a parameter of thestimulation may be adjusted such as amplitude, pulse width and/orfrequency.

Parameters which could be sensed include the activity of single neuronsas detected with microelectrode recording techniques, local fieldpotentials, event related potentials, for example in response to amemory task or sensory stimulus and electroencephalogram orelectrocorticogram. For example, U.S. Pat. No. 6,227,203 providesexamples of various types of sensors that may be used to detect asymptom or a condition of a cognitive disorder and responsively generatea neurological signal. In an embodiment, a neurochemical characteristicof the cognitive function may be sensed, additionally or alternatively.For example, sensing of local levels of neurotransmitters (glutamate,GABA, Aspartate), local pH or ion concentration, lactate levels, localcerebral blood flow, glucose utilization or oxygen extraction may alsobe used as the input component of a closed loop system. These measurecould be taken at rest or in response to a specific memory or cognitivetask or in response to a specific sensory or motor stimulus. In anotherembodiment, an electro-physiological characteristic of the cognitivefunction may be sensed. The information contained within the neuronalfiring spike train, including spike amplitude, frequency of actionpotentials, signal to noise ratio, the spatial and temporal features andthe pattern of neuronal firing, oscillation behavior and inter-neuronalcorrelated activity could be used to deliver therapies on a contingencybasis in a closed loop system. Moreover, treatment therapy delivered maybe immediate or delayed, diurnal, constant or intermittent depending oncontingencies as defined by the closed loop system.

Thus, embodiments of IMPROVING COGNITIVE FUNCTION WITHIN A HUMAN BRAINare disclosed. One skilled in the art will appreciate that the presentinvention can be practiced with embodiments other than those disclosed.The disclosed embodiments are presented for purposes of illustration andnot limitation, and the present invention is limited only by the claimsthat follow.

What is claimed is:
 1. A method for treating a human cognitive disorderselected from the group consisting of Alzheimer's disease and mildcognitive impairment (MCI) by means of an implantable signal generatorand a lead having a proximal end coupled to the signal generator and adistal portion having at least one electrode, the method comprising: (a)implanting a stimulation portion of the at least one electrode in aposition chosen to stimulate the nucleus basalis of Meynert of a brain;(b) coupling the proximal end of the lead to the signal generator; and(c) treating the cognitive disorder by operating the signal generator tostimulate the nucleus basalis of Meynert.